5α-Reduced glucocorticoids: a story of natural selection

5 alpha-Reduced glucocorticoids (GCs) are formed when one of the two isozymes of 5 alpha-reductase reduces the Delta(4-5) double bond in the A-ring of GCs. These steroids are largely viewed inert, despite the acceptance that other 5 alpha-dihydro steroids, e.g. 5 alpha-dihydrotestosterone, retain or have increased activity at their cognate receptors. However, recent findings suggest that 5 alpha-reduced metabolites of corticosterone have dissociated actions on GC receptors (GRs) in vivo and in vitro and are thus potential candidates for safer anti-inflammatory steroids. 5 alpha-Dihydro- and 5 alpha-tetrahydro-corticosterone can bind with GRs, but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However, a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the GR and recently the abilities of 5a-reduced GCs to suppress inflammation have been demonstrated in vitro and in vivo. Thus, the balance of parent GC and its 5 alpha-reduced metabolite may critically affect the profile of GR signalling. 5 alpha-Reduction of GCs is up-regulated in liver in metabolic disease and may represent a pathway that protects from both GC-induced fuel dyshomeostasis and concomitant inflammatory insult. Therefore, 5 alpha-reduced steroids provide hope for drug development, but may also act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5 alpha-reductase inhibitors, drugs that are commonly administered long term for the treatment of benign prostatic hyperplasia. Journal of Endocrinology (2012) 212, 111-127